Flavored dentifrice

ABSTRACT

There is disclosed a substantially anhydrous dentifrice which contains a dipeptide sweetener in combination with an acid anhydride. There is also disclosed a method of making the same.

This invention relates to a novel dentifrice preparation, moreparticularly to a dentifrice in which the sweetening agent whichheretofore suffered from rapid loss of sweetening upon aging in anaqueous dentifrice is stabilized by formulation into an anhydrous creamcontaining a food grade acid anhydride therein. The invention being inthe nature of an anhydrous dentifrice is succestible to the addition ofvarious water incompatible dentifrice additives, such as the presentsweetener, certain enzymes, bleaching agents, fluorides and the like.The invention also relates to methods of producing the aforesaiddentifrice.

The incorporation of certain water incompatible dentifrice additives inordinary hydrous toothpastes has not been possible because of theinstability or inactivity of these substances in the presence ofmoisture. Some fluoride additives form insoluble salts with the otheringredients in the hydrous toothpastes, thus rendering them ineffectivefor protection against caries. With other therapeutic additives,difficulties involving production and storage are encountered. As aresult, the marketing of toothpaste products containing certain of theseadditives has not been possible. Moreover, attempts to formulateanhydrous toothpastes to circumvent the water incompatibility problemhave been generally unsuccessful from the standpoint of consumeracceptance of these products.

In addition to the problems inherent in an anhydrous cream there is theadditional problem of compatibility of the flavors and sweetenersemployed in dental formulations.

It has been observed that taste and flavor are perhaps the mostimportant single aspects with respect to the consumer acceptance of adentifrice formulation. The selection of acceptable sweetener andflavoring ingredients is therefore of significant importance in theformulation of a dentifrice. It has oftentimes been stated that theforegoing is both an art as well as a science. It is an art in the sensethat it requires the blending of the various components with thesweetening agents such that the final composition contains a pleasingtaste as well as in providing for a composition in which the sweeteneris stable. It is the foregoing that has presented particulardifficulties in incorporating sweetening agents into a dentifriceinasmuch as the former must be compatible with the latter and both mustremain essentially unchanged over the shelf life of the product.

At the present time, there are relatively few sweeteners which are bothcurrently available for use in dentifrices as well as generallyacceptable for use therein. This need has stimulated the search forartificial sweetening agents which may be used as sugar substitutes. Thefirst artificial sweetener approved for general use was saccharin.Saccharin is markedly sweeter than sucrose, having a potency of 250-350times the latter, but it has been known to leave a bitter aftertaste.More recently, the sweetening property of cyclohexylsulfamic acid(cyclamate) and its sodium and calcium salts was discovered. Thosesubstances are about 30 times as sweet as sucrose, but also suffer fromcertain disadvantages.

Other more exotic sweeteners though available are generally notacceptable for use in a dentifrice due to their stability problemsvis-a-vis the various components in the dentifrice. Some of thosesweeteners which do not have stability problems have the drawback thatthey are not suitable for use as a primary sweetener due to theunacceptable timelag prior to the onset of their sweeteness and/or theirassociated side tastes.

A further consideration in formulating a dentifrice relates to the factthat the polishing agents employed therein are generally absorbentmaterials and therefore there may be a selective absorption onto thepolishing agent of the sweetener with accompanying changes in physicalform of the toothpaste, chemical changes and accordingly changes inoverall flavor.

The sweetening agent contemplated herein is a dipeptide sweetener, whichmay be characterized by the following general formula: ##EQU1## whereinR is an alkyl radical containing about 1 to 2 carbon atoms, preferablyone.

Wherein R is 1, the dipeptide sweetener may be convenientlycharacterized as aspartylphenylanaline methyl ester.

The above sweetening agents are markedly sweeter than sucrose,possessing a potency of about 50-250 times relative to that standard.They are, moreover, lacking in the unpleasant aftertaste characteristicof currently available artificial sweeteners. The sweetening agents maybe manufactured by the methods disclosed in U.S. Pat. No. 3,492,131,which is incorporated herein by reference.

The aforementioned dipeptide sweetening agents wherein R is methyl,i.e., the methyl esters, and the stereoisomers of L-L configuration areparticularly preferred for incorporation into the instant dentalformulation. L-aspartyl-L-phenylalanine methyl ester andL-aspartyl-L-hexahydrophenylalanine methyl ester thus display a potencyof about 200-250 times that of sucrose. The corresponding ethyl estersare about half as sweet.

The above sweetener has heretofore been described in the literature andeven peripherily mentioned for use in consumable toiletries such asmouthwashes and toothpaste by merely including same therein. Such dentalproducts, however, apparently never have been prepared, inasmuch as theliterature is silent on the fact that the sweetener is not by itselfstable in either an androus or aqueous dentifrice. The sweetness of thedipeptide sweetener has been found to rapidly dissipate soon (by shelflife standards) after incorporation into the dentifrice. It has beenfound that sweeteness is rapidly lost in about 1 week's time, theforegoing clearly unsatisfactory for a product that oftentimes has ashelf life of many months between factory packaging and ultimateconsumer depletion of the product.

It has been unexpectedly found that following the teachings of the priorart leads to a product wherein the primary sweetness is rapidly lost andaccordingly the dentifrice incorporating same no longer possesses asufficient degree of sweetness to mask the associated side tasteinherent in some dentifrices.

In order to incorporate same in a dentifrice there is the need tocontrol the environment of this sweetener and accordingly, thedentifrice herein is substantially anhydrous; with this requirement,there is the accompanying need to incorporate an acid-anhydride or likematerial therein so as to maintain the stability and effectiveness ofthe sweetener and be operative to combine with free water present in theraw materials. It is understood that the acid anhydride will benon-toxic and suitable for oral use. It is also to be understood thatother suitable acid functional materials may be employed, the principalguideline being that they be substantially anhydrous.

It is accordingly an object of this invention to provide for asubstantially anhydrous dentifrice containing a dipeptide sweeteningagent.

It is another object of the invention to avoid one or more drawbacks ofthe prior art.

Broadly speaking, the invention includes the provision of asubstantially anhydrous dentifrice which contains a dipeptide sweetenerin admixture with an acid-anhydride.

The dipeptide esters contemplated herein are conveniently manufacturedby methods suitable for the coupling of amino acids. An especiallypreferred starting material is the asparic acid derivative wherein theamino function is protected by a benzyloxy-carbonyl group and theB-carboxy function by a benzyl ester group, and the α-carboxy group isconverted to a p-nitrophenyl ester function. The preparation of thatsubstance, i.e., N-benzoyloxy carbonyl-L-aspartic acid α-p-nitrophenyl,B-benzyl diester, is described by S. Guttmann Helv. Chim. Acta, 44 721(1961).

The sweetening property of the dipeptide substances is partiallydependent upon the stereochemistry of the individual amino acids, i.e.,aspartic acid and phenylalamine, from which the dipeptides are derived.Each of the amino acids can exist in either the D or L form, but it hasbeen determined that the L-aspartyl - L - phenylalamine esters are sweetwhile the corresponding D - D, D-L, and L-D isomers are not.Combinations of isomers which contain the L-L dipeptide, i.e.,DL-aspartyl - L - phenylalamine, L - aspartyl - DL - phenylalamine andDL - aspartyl-DL - phenylalamine, are sweet also.

Combinations of the dipeptide sweetening agents with sugar or syntheticsweeteners such as saccharin likewise can be incorporated into dentalformulations of this invention. Lesser amounts of each sweetener are,furthermore, required as a result of the effect by such combination.

Toothpastes or creams whether dispensed from flexible or resilient tubesor from pressurized containers, such as "aerosol" dispensers, willnormally comprise polishing agents (s), vehicle (s), surface activeagent(s) or detergents(s), gelling agent(s), and various otheradjuvants, such as flavors, colorants, bactericides, tooth hardeners,e.g., fluorides or fluorine compounds, and preservatives or stabilizers.

Paste or cream dentifrices may be based on aqueous or substantiallynon-aqueous systems. The former, not included herein, will usuallyinclude substantial proportions of finely divided, solid polishingagent, surface active agent, gelling agent and some non-aqueous vehicle,e.g., glycerol, whereas the latter type will often contain a minorproportion of a particulate solid polishing agent, a larger proportionof non-aqueous vehicle, surface active agent and gelling agent, with aminor proportion of water unavoidably often being present in the rawmaterials.

The substantially anhydrous base of this invention is preferablyformulated from the following: (1) humectant or an oil; (2) a non-toxicemulsifier; (3) gelling or binding agent; (4) an abrasive orabrasive-free inert ingredient; (5) standard toothpaste additives; andoptionally, (6) water incompatible dentifrice additives.

The above-mentioned ingredients must, of course, be non-toxic andsubstantially anhydrous.

The dentifrice formulation of this invention includes liquids and solidsthat are proportioned as further defined hereinafter to form a creamymass of desired consistency which is extrudable from an aerosolcontainer or a collapsible tube (for example aluminum or lead). Ingeneral, the liquids in the dental cream will comprise chiefly glycerineor an oil, propylene glycol, polyethylene glycol 400, etc., includingsuitable mixtures thereof. It is advantageous usually to use a mixtureof both humectant and binder such as glycerine and Carbowax 600. Thetotal liquid content will generally be about 20 to 75 percent by weightof the formulation. It is preferred to use also a gelling agent indental creams and gels such as the natural and synthetic gums andgum-like materials, for example, Irish moss, gum tragacanth, methylcellulose, polyvinylpyrrolidone, hydrophilic colloidal carboxyvinylpolymers, such as those sold under the trademark Carbopol 934 and 940and synthetic silicated clays such as those sold under the trademarkLaponite CP and Laponite SP. These grades of Laponite have the formula

    [Si.sub.8 Mg.sub.5.1 Li.sub.0.6 H.sub.7.6 O.sub.24 ].sup. 0.6 Na.sup.+0.6

The solid portion of the vehicle is usually present in an amount of upto about 10 percent preferably about 0.2 to 5 percent by weight of theformulation.

The proportions of gelating agents or thickeners in the presentdentifrices are sufficient to form an extrudable, shape-retainingproduct which can be squeezed from a tube onto a toothbrush and will notfall between the bristles of the brush but rather, will substantiallymaintain its shape thereon. In almost all cases no more than about 10%of gelling agent need be used and in most instances about 0.5 to 10%will suffice, with the preferred range, especially applicable to sodiumcarboxymethyl cellulose, being from 0.5 to 1.5%.

Suitable oils for use in the practice of this invention include thosewhich have viscosity ranging from about 100 to about 300 centipoises at70°F., and can be mineral oil, light liquid petrolatum thickened to thenecessary viscosity; and vegetable oils. The preferred mineral oil isMineral Oil U.S.P. (also known as Liquid Petrolatum U.S.P., mineral oil(heavy medicinal), white mineral oil, liquid paraffin, and heavy liquidpetrolatum). Mineral oil U.S.P. is defined in Remington's PharmaceuticalSciences, 13th. edition, Mack Publishing Co., Easton, Pa. 1965 as "amixture of liquid hydrocarbons obtained from petroleum; a colorlesstransparent, oily liquid, free or nearly free from fluorescene." It istasteless and odorless when cold and develops not more than a faint odorof petroleum when heated.

The preferred light liquid petrolatum is Light Liquid Petrolatum N.F.also known as light liquid paraffin and light white mineral oil. It isdescribed in Remington's Pharmaceutical Sciences, as " . . . a mixtureof liquid hydrocarbons obtained from petroleum, it may contain astabilizer." If the Light Liquid Petrolatum N.F. is used as the oil itmust be thickened to the required viscosity of from about 100 to about300 centipoises at 70°F. with one of the well-known commerciallyavailable inert thickening materials, such as a pyrogenic silica soldunder the trademark CAB-O-SIL, or a hydrogenated castor oil, sold underthe tradename THIXIN.

Suitable vegetable oils which may be used as the oil ingredient includecoconut oil, cotton-seed oil, sesame oil and similar non-toxic vegetableoils, as described in Vegetable Fats and Oils by E.W. Eckey, ReinholdPublishing Corp., New York, 1954. The vegetable oil selected must, ofcourse, fall within the required viscosity range of from about 100 toabout 300 centipoises. A particular vegetable oil falling within thisrange is NEOBFE M-5, a fractional triglyceride of coconut oil. It isdesirable that the vegetable oil ingredient contain a minor amount of anantioxidant such as butylated hydroxyanisole or butylatedhydroxytoluene, preferably in an amount ranging from about 0.1% to about3% by weight, based on the weight of the vegetable oil employed.

The liquid vehicle of the dentifrice, together with the gelling agent(s)and other constituents, forms an extrudable mass of a non-drippingconsistency when extruded from a collapsible tube, such as an aluminumor lead tube. Thus, by the addition of more vehicle, the dental creamcan be thinned and conversely, by the addition of more solids,especially more gelling agents, the products can be thickened. In mostdentifrices, the liquid portion comprises glycerine; although it ispreferred to employ glycerol, other suitable vehicles in place thereofor in addition thereto may also be present, either with the mentionedpolyhydric alcohols or in replacement for them. Thus, propylene glycol,polyethylene glycol, mannitol and polypropylene glycol may be employedproviding that they are physiologically acceptable and produce productshaving a desired refractive index, in the case of manufacture ofvisually clear dentifrices. Normally the proportion of vehicle isdetermined by the physical properties of the extrudate. Usually,however, from about 10 to 90% of the vehicle will be employed, withabout 10 to 35% being a typical range for production of opaquedentifrices and about 40 to 90% being useful for the manufacture ofclear dental preparations.

It is to be understood that while ordinarily where sorbitol is employedin a dentifrice, it is used as an aqueous solution, sorbitol may beemployed herein, with the proviso, however, that it be substantiallyanhydrous (i.e., crystaline).

It is to be understood that the substantially anhydrous system refers tothe absence of sufficient free water to substantially adversely affectthe stability of the sweetener. There may be present relatively minorproportions of water, or water in bound form or the like which arecompatible in the system. Preferred ranges are, respectively, about 15to 30% of the polyhydric alcohols for the opaque dentifrices and about50 to 75% in the clear products.

In the preparation of tooth powders, it is usually sufficient to admixmechanically, e.g., by milling, the various solid ingredients, inappropriate quantities and particle sizes, and thereafter carrying outprocedures known in the art for containerization of the product.

In chewable dental tablets the solids and liquids are proportionedsimilarly to the amounts in dental creams and the flavor is blended withthe solids and liquids, a waxy matrix such as polyethylene glycol havinga molecular weight of about 6,000 by weight, generally in amount ofabout 4-20 percent by weight, in order to facilitate forming a tablet ofdesired size and shape.

In addition, the formulation will generally include a dentallyacceptable, substantially water insoluble, polishing agent of the typecommonly employed in dental creams. The polishing agents are usuallyfinely divided water insoluble powdered materials of particle sizes suchthat they pass a 140 mesh screen, U.S. Standard Sieve Series.Preferably, they are from 1 to 40 microns, most preferably from 2 to 20microns in particle sizes, with distribution of particle sizes beingnormal over the range. Representative polishing agents include, forexample, dicalcium phosphate, tricalcium phosphate, insoluble sodiummetaphosphate, aluminum hydroxide, including hydrated alumina, colloidalsilica, magnesium carbonate, calcium carbonate, calcium pyrophosphate,bentonite, etc., including suitable mixtures thereof. When employed, itis preferred to use the water insoluble phosphate salts as the polishingagent and more particularly insoluble sodium metaphosphate and/or acalcium phosphate such as dicalcium phosphate dihydrate in dentalcreams.

The above listing of polishing agents, and other listings of otherconstituents of the dentifrice composition to be given in the presentspecification are not intended to be exhaustive and therefore, for othermaterials of these types reference should be made to a standardhandbook, such as Cosmetics: Science and Technology, by Sagarin, 2ndprinting, 1963, published by Interscience Publishers, Inc. Most of thepolishing agents mentioned are most useful in the preparation of opaquedentifrices but some of them, such as the colloidal silicas, especiallythe silica xerogels, and complex sodium aluminosilicates, such as thosesold under the trademark Syloid as Syloid 72 and Syloid 74 or under thetrademark Santocel as Santocel 100 and synthetic alkali metalaluminosilicate complexes may be particularly useful, in the manufactureof clear dentifrices, because their indexes of refraction approximatethose of the rest of the dentifrice constituents in an appropriatevehicle, i.e., of the gelling agent-liquid (generally includinghumectants such as glycerine and sorbitol) systems commonly used indentifrices.

The content of polishing agent in the final dentifrice product isvariable, generally being greater for the opaque than for thetranslucent or transparent dental gels. For example, in the manufactureof commercially acceptable opaque form-retaining, extrudable dentalcreams there usually will be present about 20 to 75% of polishing agent,e.g., dicalcium phosphate, but in the manufacture of clear dental gels,also form-retaining and extrudable, the content of polishing agent istypically about 5 to 40%. The preferred proportions of such constituentsare about 40 to 60% and about 10 to 30%, respectively. In the case ofthe polishing agent for opaque products, a most preferred compositionincludes hydrated dicalcium phosphate and anhydrous dicalcium phosphate,with the latter being present to the extent of about 5 to 20% of thetotal dicalcium phosphate content. With respect to the transparent ortranslucent dental gels, either sodium aluminosilicate complex or silicaxerogel will usually be employed separately, although mixtures thereofmay find special advantages in some products where the desired polishingproperties may be so regulated. It will be seen that the polishingagents utilized in accordance with the invention are normally waterinsoluble inorganic metal oxides, hydroxides, salts and hydrates butwater insoluble organic compounds may also be employed in substitutionthereof, although usually for only minor proportions of the totalpolishing agent. For example, polyacrylamides, polymethyl methacrylates,polyesters and nylons may be utilized.

Of the water-insoluble polishing agents, most are well known chemicalcompounds. The complex aluminosilicate salts, which appear to containinterbonded silica and alumina having Al-O-Si bonds, are described byTamele, in "Chemistry of the Surface and the Activity of Aluminum-SilicaCracking Catalysts", appearing in Discussions of the Faraday Society,No. 8, pages 270-279 (1950), particularly at page 273, FIG. 1, Curve 3,and in the article by Milliken et al, entitled "The ChemicalCharacteristics and Structure of Cracking Catalysts", in Discussions ofthe Faraday Society, No. 8, 279-290 (1950), particularly in the sentencebridging pages 284 and 285. The colloidal silicas used are silicaAerogels. Typically they have a refractive index of about 1.44 to 1.47and a loose bulk density of about 0.07 to 0.12 g./c. cm. and are ofparticle sizes of 1 to 20 microns. Appropriate aerogels have beenmarketed under the trademarks Syloid 63 and Syloid 74.

Organic surface-active agents are used in the compositions of thepresent invention to assist in achieving thorough and completedispersion of the instant compositions throughout the oral cavity andrender the instant compositions more cosmetically acceptable. Theorganic surface-active material may be anionic, nonionic, ampholytic, orcationic in nature, and it is preferred to employ as the surface-activeagent a detersive material which imparts to the composition detersiveand foaming properties. Suitable such detergents are water-soluble saltsof higher fatty acid monoglyceride monosulfates, such as the sodium saltof the monosulfated monoglyceride of hydrogenated coconut oil fattyacids, higher alkyl sulfates, such as sodium lauryl sulfate, alkyl arylsulfonates, such as sodium dodecyl benzene sulfonate, higher alkylsulfoacetates, higher fatty acid ester of 1,2-dihydroxy propanesulfonates, and the substantially saturated high aliphatic acyl amidesof lower aliphatic amino carboxylic acid compounds, such as those haing12 to 16 carbon atoms in the fatty acid, or acyl radicals, and the like.Examples of the last mentioned amides are N-lauroyl sarcosine, and thesodium potassium and ethanolamine salts of N-lauroyl, N-myristoyl, orN-palmitoyl sarcosine which should be substantially free from soap orsimilar higher fatty acid material which tends to substantially reducethe effect of these compounds. The use of these sarcosinate compounds inthe dentifrice compositions of the present invention is particularlyadvantageous since these materials exhibit a prolonged and marked effectin the inhibition of acid formation in the oral cavity due tocarbohydrate breakdown in addition to exerting some reduction in thesolubility of tooth enamel in acid solutions.

Other particularly suitable surface active materials include nonionicagents such as condensates of sorbitan monostearate with approximately20 moles of ethylene oxide, condensates of ethylene oxide with propyleneoxide, condensates of propylene glycol ("Pluronics"), and amphotericagents such as quaternized imidazole derivatives which are availableunder the trademark "Miranol" such as Miranol C₂ M.

Other suitable nonionic detergents are the condensation products of anα-olefin oxide containing 10 to 20 carbon atoms, a polyhydric alcoholcontaining 2 to 10 carbons and 2 to 6 hydroxyl groups and eitherethylene oxide or a heteric mixture of ethylene oxide and propyleneoxide. The resultant detergents are heteric polymers having a molecularweight in the range of 400 to about 1600 and containing 40% to 80% byweight of ethylene oxide, with an α-olefin oxide to polyhydric alcoholmole ratio in the range of about 1:1 to 1:3. These detergents aremanufactured using well-known polymerization techniques under conditionsof high temperature and high pressure. The olefin oxide and polyhydricalcohol usually are added to the reactor prior to the addition ofethylene oxide. These nonionic detergents may be mixed with similarnonionic detergents as well as other types nonionic detergents describedherein.

There may also be employed olefin sulfonate detergents, typically longchain alkenyl sulfonates.

The α-olefin feedstock preferably contains olefins of 8-25 carbon atoms,most preferably 12-21 carbon atoms. The feedstock may contain minoramounts of other constituents, such as secondary or internal olefins,diolefins, cyclic olefins, aromatics, naphthalenes, and alkanes. Bestresults have been obtained when α-olefins (where R₁ is H) constitute amajor proportion. A typical olefin feedstock contains in the range ofabout 12 to 21 carbon atoms in the molecule and yields olefin sulfonateshaving excellent detegency properties. Especially good foamingcharacteristics have been obtained by the use of a feedstock whoseα-olefin content consists essentially of compounds of 15 to 18 carbonatoms.

The detergent material above produced typically contains at least about50% by weight of long-chain alkenyl sulfonate, up to about 33% by weightof hydroxy alkane sulfonate, and up to about 15% of impurities, such aslong chain water-insoluble sultones, most of which impurities arecharacterized as being soluble in acetone.

The olefin sulfonate is generally employed in the form of its sodiumsalt. It is within the scope of this invention to use otherwater-soluble salts, for example, salts of other alkali metals such aspotassium salts of alkaline earth metals, such as magnesium and calcium,triethanolamine, salts and the like as well as mixtures of a salt suchas a sodium salt with the free olefin sulfonic acid.

It is preferred to use from about 0.05 to 5% by weight of the foregoingsurface-active materials in the instant oral preparations.

Various other compatible and suitable materials may be incorporated inthe dentifrice formulations of this invention. Examples thereof arecoloring or whitening agents or dyestuffs, preservatives, silicones,chlorophyll compounds, ammoniated materials such as urea, diammoniumphosphate and mixtures thereof, and other constituents. These adjuvantsare incorporated in the instant compositions in amounts which do notsubstantially adversely affect the properties and characteristicsdesired and are selected and used in proper amount depending upon theparticular type of preparation involved.

The compositions of the present invention may also contain afluorine-containing compound having a beneficial effect on the care andhygiene of the oral cavity, e.g., dimunition of enamel solubility inacid and protection of the teeth against decay. Examples thereof includesodium fluoride, stannous and manganese fluoride, potassium fluoride,potassium stannous fluoride (SnF₂ KF), potassium fluorozirconate, sodiumhexafluorostannate, stannous chlorofluoride, and sodiummonofluorophosphate. These materials which dissociate or releasefluorine-containing ions, suitably may be present in an effective butnon-toxic amount usually within the range of about 0.1 to 1% by weight,based on the water-soluble fluorine content thereof. Sodium fluoride,stannous fluoride, and sodium monofluorophosphate are particularlypreferred, as well as mixtures thereof.

Antibacterial agents may also be employed in the oral preparation of theinstant invention to provide a total content of such agents of up toabout 5% by weight, preferably about 0.01 to 5.0%, most preferably about0.05 to 1.0%. Typical antibacterial agents include:

N¹ -(4-chlorobenzyl)-N⁵ -(2,4-dichlorobenzyl) biguanide;

p-chlorophenyl biguanide;

4-chlorobenzhydryl biguanide;

4-chlorobenzhydrylguanylurea;

N-3-lauroxpropyl-N⁵ -p-chlorobenzylbiguanide;

1(lauryldimethylammonium)-8-(p-chlorobenzyldimethylammonium) octanedichloride;

5,6-dichloro-2-guanidinobenzimidazole;

N¹ -p-chlorophenyl-N⁵ -laurylbiguanide;

1,6-di-p-chlorophenyl biguanidohexane;

1,6-bis(2-ethylhexyl biguanido) hexane;

5-amino-1,3-bis(2-ethylhexyl)-5-methylhexahydropyrimidine;

and their non-toxic acid addition salts.

Synthetic finely divided pyrogenic silica such as those sold under thetrademark Cab-O-Sil M-5, Syloid 244, Syloid 266 and Aerosil D-200 mayalso be employed in amounts of about 1-5% by weight to promotethickening or gelling and to improve clarity of the dentifrice.

The taste of the new compositions may be modified by employingadditional suitable flavoring or sweetening materials, which compatiblematerials may be blended into the dental vehicle along with the othermaterials heretofore mentioned.

The flavors which may be used include flavoring agents which may be insolid or liquid form. Most of such agents will be essential oils but theflavors may also include various flavoring aldehydes, esters, alcoholsand similar materials, often the higher fatty compounds, known in theart. Examples of the essential oils include oils of spearmint,peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram,cinnamon, lemon lime, grapefruit and orange. Also useful are suchchemicals as menthol, carvone and anethole. Of these, the most commonlyemployed are the oils of peppermint, spearmint, and eucaluptus andanethole, menthol and carvone. In some cases flavorful solvents, such aschloroform and mock chloroform, may be employed. Such flavorings may beused as liquids or may be solidified by being mixed with a particulatecarrier material, such as starch, calcium carbonate, paraffin, vegetablewax, fat, higher fatty acid or other suitable carrier substances. In thecases of solid flavors, such as vanillin, sage, citric acid or licorice,the flavor may be converted to liquid form, if so desired, by dissolvingit in the solvent or emulsifying it, usually with the help of asynthetic or natural emulsifying agent. The choice as to whether toutilize particulate solid or liquid flavors or to convert such flavorsto a particulate solid or liquid form, respectively, will often dependon the properties desired in the flavor and its compatibility with thesweetener and any other material to be present with it. Thus, wherechemical interactions with the acid anhydride and/or the sweetener areto be avoided it may well be desirable to utilize only solid compatibleflavors but in those cases where reactions are not probable orobjectionable, liquids may be used. Of course, even in the cases ofliquids, the thickness of the liquid may be adjusted by utilization ofgelling agents or thickeners, usually to the extent of less than about10% of the flavor, preferably about 1 to 10% thereof. Similarly, thesolid particles will have a viscosity of about 0.1 to 1,000 centipoises,preferably about 0.5 to 10 centipoises and the particle sizes will beabout 0.1 micron to one millimeter, preferably about 1 to 100 microns indiameters.

The dipeptide sweetener will usually be a minor proportion of the totaldentifrice product, preferably about 0.1 or 0.5 to 10% thereof. The acidanhydride will generally be included in amounts of about 0.1 to 15.0%,preferably 0.1 to 1.0% and most preferably 0.25 to 0.5% by weight. Ofcourse, the percentages of adjuvants or other materials also present maybe regulated for best results and usually will be about 0.2 to 5 timesthe weight of the sweetener. The proportion of additional sweetenerwhere desired in the dentifrice or flavor will normally be about 0.1 to2% of the entire product, preferably about 0.5 to 1.5% thereof.

It is believed that the acid anhydride functions to maintain the acid pHintegrity (about 3-5) of the sweetener, help to absorb excess free waterpresent and thereby provide for maximum stability of the sweetenerwithout the occassionally needed step of making major changes in theacidity of the dentifrice vehicle. Suitable acid anhydrides include butare not limited to the food acidulents, such as acetic-, succinic-,adipic-, fumaric-, lactic-, malic acid and the like; vitamin and aminoacids, such as folic-, ascorbic-, aspartic and the like; anti-microbialacids such as benzoic acid and the like; synthetic flavoring acids, suchas isovaleric-, phenoxyacetic acid and the like; chelating acids, suchas citric-, tartaric acid and the like; inorganic acids, such asorthophosphoric acid and the like; and fatty acids, such as lauric-,stearic acid and the like; and compatible mixtures thereof. Additionaloperative examples of the acids falling within the above describedgroupings may be found in The Handbook of Food Additives, published bythe Chemical Rubber Company, 1968; the foregoing is incorporated hereinin its entirety by reference.

Because the mouth is substantially aqueous environment the flavorsutilized will normally be water-soluble, emulsifiable or dispersible.

The invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only and it will beunderstood that the invention is not to be construed as limited eitherin spirit or in scope by the details contained therein as manymodifications both in materials and methods will be apparent from thisdisclosure to those skilled in the art. In the examples and the appendedclaims, quantities of materials are expressed in parts, proportions orpercentages by weight except where otherwise noted.

                  EXAMPLE                                                         ______________________________________                                                              Parts                                                   ______________________________________                                        Glycerin                58.69                                                 Carbowax 600 (polyethylene glycol-                                                 Union Carbide)     3.00                                                  Aspartyl phenyl alanine methyl ester                                                                  0.40                                                  Succinic anhydride      0.50                                                  Benzoic acid            0.15                                                  Sodium monofluorophosphate                                                                            0.76                                                  Na Aluminum Silicate    30.00                                                 Silica Aerogel          4.00                                                  Na Lauryl Sulfate       1.50                                                  Flavor                  1.00                                                  ______________________________________                                    

The above materials are formulated in the usual manner into anextrudible toothpaste.

EXAMPLE 2

Example 1 is repeated with the same materials except that the followingvariations are made.

In addition to the methyl ester sweetener present at 0.3%, there is alsopresent 1.0% flavor of spearmint and present with the spearmint is about0.1% of sodium saccharin and 0.02 of green colorant (F.D. & C. Green No.3) of the water-soluble type.

EXAMPLES 3-4

The procedure of examples 1 and 2 are repeated, however, theformulations are varied as follows.

                  EXAMPLE 3                                                       ______________________________________                                        DENTAL CREAM                                                                                        Parts                                                   ______________________________________                                        Syloid 244              3.0                                                   Antimicrobial agent     0.1                                                   Sodium benzoate          0.15                                                 Aspartylphenylalanine methyl ester                                                                     0.20                                                 Sodium lauryl sulfate   1.5                                                   Insoluble sodium metaphosphate                                                                        38.6                                                  Dicalcium phosphate dihydrate                                                                         5.0                                                   Titanium dioxide        0.4                                                   Stannous fluoride       0.4                                                   Gum tragacanth          0.4                                                   Oil of wintergreen      1.0                                                   Color                    0.03                                                 Stearic anhydride        2.00                                                 Glycerine (99.3%)       27.10                                                 ______________________________________                                    

This composition is used by brushing the teeth therewith at least oncedaily.

In the above dental cream, the sodium lauryl sulfate may be replaced bysodium-N-lauroylsarcosinate.

                  EXAMPLE 4                                                       ______________________________________                                        DENTAL CREAM                                                                                         Parts                                                  ______________________________________                                        Antimicrobial agent      0.1                                                  Aspartylphenylalanine methyl ester                                                                     0.2                                                  Sodium benzoate          0.5                                                  Sodium acid pyrophosphate                                                                               0.25                                                Cab-O-Sil                2.00                                                 Dicalcium phosphate dihydrate                                                                          35.25                                                Calcium carbonate        5.0                                                  Sodium carboxymethylcellulose                                                                           0.25                                                Olefin sulfonate         2.0                                                  Glycerine (99.3%)        23.95                                                Oils of peppermint and spearmint, 1:1                                                                  0.8                                                  Benzoic anhydride        3.0                                                  ______________________________________                                    

In other experiments, the flavor(s) are changed to eucalyptus, anethole,menthol and carvone and the proportions are varied over the 0.5 to 5%range, with similar results. Generally, however, the total amount offlavoring employed will be about 0.5 to 2% based upon the totaldentifrice, for best taste effects.

                  EXAMPLE 5                                                       ______________________________________                                                                 Parts                                                ______________________________________                                        Glycerine (99.5% C.P.)     17.0                                               Cab-O-Sil                  1.0                                                Aspartylphenylalanine methyl ester                                                                       1.0                                                Succinic anhydride         14.5                                               Hydrated alumina, (2 to 20 microns in dia.)                                                              55.0                                               Sodium N-lauroyl sarcosine 2.0                                                Glycerine (99.5% C.P.)     2.9                                                Dental cream flavoring (essential                                             oils, sweeteners, esters)  1.2                                                ______________________________________                                    

The above opaque dental cream is made by a method corresponding to thatof Example 1.

EXAMPLE 6

The procedure of Example 2 is followed, utilizing the formula givenbelow, to make a clear gel dentifrice.

    ______________________________________                                        Components:              Parts                                                ______________________________________                                        Mannitol                 75.0                                                 Glycerine                25.0                                                 Laponite SP              2.0                                                  Sodium N-lauroyl sarcosinate                                                                           2.0                                                  Aspartylphenylaniline methyl ester                                                                     0.1                                                  Aerosil D200             3.0                                                  Sodium aluminumsilicate  16.0                                                 Flavor                   1.0                                                  Color                    1.0                                                  Succinic anhydride       3.0                                                  ______________________________________                                    

The sodium aluminumsilicate employed is a complex having a refractiveindex of about 1.46, a moisture content of about 6 percent, an averageparticulate size of about 35 microns and a sieve loose bulk density ofabout 0.07 g./cc.

The various parts of the formulation are blended together in the mannerdescribed with respect to the preceding examples.

The product resulting is of excellent clarity and taste and when it hascoloring materials such as F.D. & C. Blue No. 1 added to it, to theextent of 10% of the sweetener, gives a product a distinctiveappearance.

EXAMPLE 7

The procedure of Example 1 is followed for the production of atransparent cream.

                           Parts                                                  ______________________________________                                        Glycerine                25.00                                                Sodium carboxymethylcellulose                                                                          0.70                                                 Aspartylphenylalanine methyl ester                                                                     0.17                                                 Sodium benzoate          0.50                                                 Sorbitol                 44.83                                                Benzoic anhydride        2.0                                                  Sodium aluminum silicate 16.00                                                Syloid 244               5.00                                                 Flavor                   1.00                                                 Sodium lauryl sulfate    2.00                                                 ______________________________________                                    

The invention has been described with respect to various examplesthereof but it is clear that such examples and previously givenillustration are not limitative, since one of ordinary skill in the artwill be able to employ substitutes and equivalents without departingfrom the inventive concept.

I claim:
 1. An anhydrous dentifrice which contains about 10 to 90% byweight of a liquid vehicle including a hydroscopic humectant, about 0.1to 10% by weight of a dipeptide sweetner selected from the groupconsisting of L-aspartyl-L-phenylalanine methyl sweetener ethyl estersand L-aspartyl-L-hexahydrophenylalanine methyl and ethyl esters inadmixture with about 0.1 to 15% by weight of a non-toxic acid anhydrideselected from the group consisting of acetic-, succinic-, adipic-,fumaric-, lactic-, malic-, folic-, ascorbic-, aspartic-, benzoic-,isovaleric-, phenoxyacetic-, citric-, tartaric-, orthophosphoric-,lauric- and stearic acids and compatible mixtures thereof whereby theacid pH integrity of said sweetener is maintained about 3 to 5 andexcess-free water present is absorbed thereby providing the stability insaid sweetener.
 2. A dentifrice according to claim 1 wherein thedipeptide sweetener is a L-aspartyl-L-phenylalanine methyl ester.
 3. Adentifrice according to claim 1 which is a toothpaste and includes apolishing agent.
 4. A dentifrice according to claim 3 which includesabout 5 to 75% of said polishing agent.
 5. A dentifrice according toclaim 4 which also includes from 0.5 to 10% of a gelling agent and 0.5to 5% of a synthetic organic detergent and in which the polishing agentis selected from the group consisting of sodium aluminum silicate,hydrated alumina, dicalcium phosphate, silica xerogel and calciumcarbonate and mixture thereof, and a vehicle selected from the groupconsisting of mannitol, sorbitol, glycerine and mixtures thereof, thegelling agent is selected from the group consisting of sodiumcarboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol,Irish moss and silica aerogel and mixtures thereof and the syntheticorganic detergent selected from the group consisting of water-solublehigher fatty acid salts and synthetic anionic and nonionic detergents.6. A dentifrice according to claim 5 which contains therein, apart fromsaid sweetener, about 0.1 to 2% of a flavoring material.
 7. A dentifriceaccording to claim 3 additionally containing 0.1 to 3.0% of a furthersweetening agent.
 8. A dentifrice according to claim 3 additionallycontaining 0.1 to 10% of a combination of flavoring oils and sweeteningagents in said vehicle.
 9. A dentifrice as defined in claim 3 whereinsaid polishing agent is water-insoluble.
 10. A dentifrice as defined inclaim 1 further containing an effective amount of an anti-bacterialagent.
 11. A dentifrice as defined in claim 3 wherein said polishingagent is about 20-95 percent by weight of the vehicle.
 12. A dentifriceas defined in claim 1 additionally containing a surface-active agent.13. A dentifrice as defined in claim 12 wherein said surface-activeagent is selected from the group consisting of water-soluble sulfates ofcompounds having long chain alkyl radicals and α-olefin sulfonates. 14.A dentifrice according to claim 11 in clear gel form, containing apolishing agent of approximately the same index of refraction as thebalance of the dentifrice.
 15. A dentifrice as defined in claim 1wherein said hydroscopic humectant is selected from the group consistingof glycerine, glycerol, propylene glycol, polyethylene glycol, mannitol,substantially anhydrous sorbitol, light liquid petrolatum, mineral oil,vegetable oil, and suitable mixtures thereof.